The treatment of CMV still poses challenging to treating physicians due to the side effects of available medicines and the occurrence of CMV drug resistance [1,2]

The treatment of CMV still poses challenging to treating physicians due to the side effects of available medicines and the occurrence of CMV drug resistance [1,2]. In kidney transplant recipients with an intermediate-to-high risk of contracting CMV infections, VGC has been established like a prophylactic and preemptive treatment and is still the 1st line-therapy for CMV infections after allo-HSCT and KTx [3,5]. The dose reduction in immunosuppressive treatment should be evaluated in patients suffering from CMV infection to strengthen cellular immunity, but this will come at the risk of graft rejection [5]. effects often lead to dose reduction, causing subtherapeutic levels, long term therapy duration, and improved risk for the development of drug resistance [2,4]. Additionally, CMV-specific intravenous immunoglobulins (CMV IVIg) are authorized as prophylactic therapy in Europe and can be considered as prophylactic treatment option after allo-HSCT and KTx [5]. Since 2018, letermovir (LMV) has also been approved like a prophylactic treatment following allo-HSCT in CMV-seropositive individuals [6]. In KTx, the prophylactic use of LMV shown a similar level of performance, but had less severe side effects than the standard-of-care therapy with VGC [7]. Nonetheless, the therapeutic use of LMV remains off-label Araloside X in allo-HSCT and KTx recipients [8]. Monitoring the cellular CD4+ and CD8+ T-cell response is an upcoming issue after HSCT and KTx [9]. In individuals after KTx, low CMV-specific T-cell reactivity was associated with a risk of CMV reactivation at the end of CMV prophylaxis [10]. In addition, low T-cell response against CMV in solid organ transplantation (SOT) and in HSCT was associated with complicated CMV treatment programs, triggering CMV resistance [11,12]. In this case series, we statement our single-center experience of a therapeutic combination of LMV, VGC/GCV, and CMV IVIg for complicated programs of CMV illness after allo-HSCT and KT. We also present Araloside X the diagnostic testing by ELISPOT (enzyme-linked immunospot) using the T-SPOT.CMV assay (Oxford Immunotec, Milton, Oxford, UK) to assess specific cellular immunity to CMV. The retrospective data collection was authorized by the institutional review table (21-1171) and all patients offered their written educated consent. 2. Materials and Methods CMV DNA was recognized in whole blood using a GeneProof CMV PCR Kit (Medac GmbH, Wedel, Germany). The PCR for CMV DNA in the blood was carried once per time point and individual together with a positive and negative control to verify the result. Anti-viral drug resistance screening against VGC/GCV, FOS, CDV, and LMV was performed by amplification and sequencing of UL-97, UL-54, and UL-56. Interpretation was based on the bioinformatic tool MRA (mutation resistance analyzer) developed by the Institute of Virology of the University or college Hospital of Ulm, Germany (https://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/mra/app/index.php?plugin=contact, accessed on 29 July 2021). IFN–producing T-cells (CD4+ and CD8+) reactive against CMV IE-1 and pp65 antigens were measured from the T-SPOT.CMV (IFN- launch assay, Oxford Immunotec, Milton, Oxford, UK), according to the manufacturers instructions. 3. Clinical Instances Case 1: A 57-year-old CMV-positive male patient who had been diagnosed with acute myeloid leukemia (AML) underwent allo-HSCT from a matched unrelated CMV-positive donor 4 weeks after diagnosis. At the time of allo-HSCT, he was in cytomorphological total remission after 2 cycles of 7 + 3 (cytarabine and daunorubicin) induction and one consolidation cycle with high-dose cytarabine. Under 7 + 3 therapy, the patient suffered from drug-induced harmful acute kidney injury. On day time +41 after transplantation, CMV DNA tested positive, and the patient received intravenous GCV, which was replaced by oral VGC after the viral weight started decreasing. After the termination of therapy, CMV-associated colitis was diagnosed on day time +113 by biopsy and offered clinically as diarrhea. Due to the severity of his CMV end-organ disease, immunosuppression was reduced and the patient was treated again with intravenous GCV; however, an increasing level of CMV viremia was observed. A mutation of UL-97, confirming resistance to VGC/GCV, was recognized, but the analysis of the T-cell immune response to CMV by ELISPOT assay Araloside X showed adequate reactivity. As foscarnet and cidofovir come with an unfavorable security profile in a patient with acute kidney injury, a combination therapy of intravenous IVIg and oral LMV (480 mg/d) was added to VGC/GCV therapy (which was maintained to prevent LMV resistance) and stable CMV clearance was accomplished. LMV was discontinued 636 days after transplantation (Number 1a). Open in a separate window Open in a separate window Number 1 Post-transplantation dynamics of CMV viremia, immunosuppressive therapy, cellular immunity against CMV (T-SPOT.CMV Elispot assay by Oxford Immunotec), antiviral Araloside X strategies and clinical program in three individuals after transplantation. X-axis: days after transplantation. (a) Case 1. AllogeneicChematopoietic stem cell transplantation Rabbit Polyclonal to OR2B6 (allo-HSCT) recipient (HLA 10/10 MUD; CMV serostatus D+/R+; ABO compatible). (b) Case 2. Kidney transplantation (KTx) from deceased donor (HLA MM A-1, B-2, DR-2; CMV serostatus D+/R?; Abdominal0 compatible). (c) Case 3. Kidney transplantation from living donor (HLA MM A-0, B-1, DR-1; CMV serostatus D?/R?; ABO compatible). Abbreviations: ATG, Anti-Thymocyte Araloside X Globulin; DR, dose reduction; GCV, ganciclovir; CMV-IVIg, CMV-intravenous immunoglobulin; IE1, immediate-early 1; LMV, letermovir; MMF, mycophenolate mofetil; pp65, phosphoprotein 65; VGC, valganciclovir CMV-DNA was recognized.